This invention relates to oral dosage forms of hormones and methods for their delivery to subjects needing hormone therapy.
Micronized progesterone formulations have been disclosed in the past Maxson et al., which discloses various progesterone oral formulations where the first major indgredient is micronized progesterone and xe2x80x9c[t]he second major component of the present invention is an oil which serves as a vehicle for the micronized progesterone. The composition and properties of the oil employed as the vehicle have a large effect on the effectiveness of the product.xe2x80x9d In addition, micronized progesterone has been dissolved or dispersed in a variety of oils to overcome the solubility problem. One commercially available oil-based oral formulation of micronized progesterone is available under the trademark Prometrium(copyright). Salin-Droumn, U.S. Pat. No. 6,077,531, states in its Abstract that it provides xe2x80x9c[a] medicament consisting of a biological medium-soluble capsule containing a micronised progesterone suspended in oil is disclosed, characterised in that the capsule also contains estradiol enclosed in microspheres, also suspended in oil, and which consist of one or more polymers that do not dissolve in oil but that dissolve in a biological medium.xe2x80x9d
In addition to the oil based preparations, various oral progesterone formulations have been proposed:
Agnus et al., U.S. Pat. No. 6,086,916, col. 1, line 56-col. 2, line 4, discusses Gram [Novo Nordisk ]WO 95/05807 as xe2x80x9cdescrib[ing] tablets containing progesterone and a polyethylene glycol, as well as an excipient chosen from the group containing starches, starch-containing components, modified starches, celluloses, modified celluloses, pectins and tragacanth. [T]he presence of polyethylene glycol and of the excipient in the tablets results in a favourable effect on the bio-availability of orally administered progesterone. * * * [T]he tablets * * * contain high percentages of excipients.xe2x80x9d Gram""s Abstract states that she provides an oral progeseterone that xe2x80x9cmay, conveniently, contain a PEG, and a further excipient selected from the group comprising a starch, a cellulose, pecting, and tragacanth.xe2x80x9d The polyethylene glycols are referred to as xe2x80x9cliquid or solid polymersxe2x80x9d. Page 7, lines 20-22. Examples with progesterone and estradiol include maize starch, lactose, polyethylene glycol 6000, croscarmellose sodium, magnesium stearate and taclum powder.
Agnus ""916 itself has an an object progesterone dosage forms that also include xe2x80x9cdiluents, disintegrating agents, lubricants and binding agents.xe2x80x9d Col. 2, lines 36-37. xe2x80x9cAs examples of diluents, mention may be made of starches, polyols and celluloses * * * preferably pregelatinized maize starch, mannitol and microcrystalline cellulose.xe2x80x9d Id., lines 38-42. Polyvinylpyrrolidone is said to be the preferred binding agent.
Agnus WO 99/45932 is stated in the English abstract to be xe2x80x9cconcern[ed with] a pharmaceutical based on natural synthesis progesterone and [ ]estradiol in tablet form, [where] its disintegration time is less than 15 minutes, preferably less than 10 minutes, and more preferably less than 5 minutes.xe2x80x9d The progesterone used in the formulation is micronized (page 8, Tableau 1, first ingredient). The example has a 9:1 weight ratio of hydroxypropylmethylcellulose:polyethylene glycol 600, where the total quantity of this mixture is 2.0 mg per unit vis a vis 14 mg. sodium carboxymethylcellulose (3.20 mg. in two different forms).
Bair, WO 97/46242, Example 3, discloses gelatin capsules containing a powder of micronized progesterone in calcium carbonate. The micronized progesterone:calcium carbonate is in a 1:4 weight ratio that has been xe2x80x9cplaced in a grinding mill and blended to yield a homogenous powderxe2x80x9d (id., lines 26-27); the powder is administered from a gelatin capsule administered five times per day.
Place, U.S. Pat. No. 6,117,446 and several continuing applications based thereon discloses a buccal dosage unit form for active agents, including progesterone and an estrogen; the examples use a polyethylene oxide and carbomer.
Dittgen et al., U.S. Pat. No. 6,117,450 disclose four differing compressed compositions to be jointly used in an oral dosage form. Example 1 delivers progesterone and estradiol in lactose; one of the four compressed compositions also uses hydroxypropylmethylcellulose and all use a polyvinyl propylene.
Polyethylene glycol has long been known as a polymer matrix for delivery of a wide variety of drugs. Snipes, U.S. Pat. No. 4,629,621, seeks to improve the use of polyethylene glycol by teaming it with an xe2x80x9cerosion rate modifier [which] is an insoluble amphiphile * * * , which slows down the rate at which the matrix is eroded * * * .xe2x80x9d Col. 3, lines 16-23. Examples given are xe2x80x9cC12-C20 fatty acids * * * , C12-C20 alcohols * * * , amphiphilic esters of fatty acids with glycerol * * * , C12-C20 amines * * * , and amides of C12-C20 fatty acids. Col. 4, lines 1-10.xe2x80x9d
In a first embodiment, there is provided an oral dosage form suitable to deliver a combined dosage of progesterone and which upon delivery through the gastrointestinal tract provides a blood concentration of from about 0.1 ng/ml to about 400 ng/ml progesterone; said dosage form comprising a combination that includes (a) a first solid form comprising from about 25 mg to about 500 mg micronized progesterone in a solid polyethylene glycol carrier having an average molecular weight of from about 1000 to 10,000 and constituting at least about 30% of said first solid form; and (b) a second solid form comprising an estrogen. In one embodiment, the polyethylene glycol carrier comprises from about 45% to about 65% weight of the first solid form. In a further embodiment, the second solid form (b) contains from about 0.25 mg to about 5 mg of estradiol.
In a further embodiment, the solid polyethylene glycol carrier comprises a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000. In a preferred embodiment there is provided an oral dosage form suitable to deliver a combined dosage of progesterone and an estrogen via the gastrointestinal tract which upon oral administration provides a blood concentration of from about 0.1 ng/ml to about 400 ng/ml progesterone; said dosage form comprising a combination that includes (a) a first solid form containing from about 25 mg to about 500 mg micronized progesterone, said caplet having been derived from the extrusion of a polymer matrix extruded from a mixture comprising micronized progesterone in a solid polyethylene glycol carrier which is a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000, the micronized progesterone having first been dispersed in molten cooling to a solid form, having extruded, said mixture constituting from about 45% to about 65% weight of said first solid form; and (b) a second solid form which contains from about 0.25 mg to about 5 mg of estradiol. In a preferred embodiment, the oral dosage form is provided with said first solid form as a caplet and said second solid form as a tablet.
In a second aspect of the invention, there is provided a method of providing an oral dosage of a combination therapy of progesterone and estradiol which comprises administering to a patient an oral dosage form suitable to deliver a combined dosage of progesterone and an estrogen via the gastrointestinal tract which upon oral administration provides a blood concentration of from about 0.1 ng/ml to about 400 ng/ml progesterone; said dosage form comprising a combination that includes (a) a first solid form containing from about 25 mg to about 500 mg micronized progesterone, said caplet having been derived from the extrusion of a polymer matrix extruded from a mixture comprising micronized progesterone in a solid polyethylene glycol carrier which is a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000, the micronized progesterone having first been dispersed in molten polyethylene glycol and, after cooling to a solid form, having been extruded, said mixture constituting from about 45% to about 65% weight of said first solid form; and (b) a second solid form which contains from about 0.25 mg to about 5 mg of estradiol.
The invention features a solid oral dosage form of progesterone comprising a therapeutically effective amount of micronized progesterone and a solid polymeric carrier, wherein the dosage form, upon oral administration, provides a therapeutically effective amount of progesterone to a subject. A preferred solid polymeric carrier is a mixture of polyethylene glycols of molecular weight ranging from about 1,000 to about 10,000. Preferably, progesterone dosage forms of this invention can be prepared by injection molding techniques. Further, the dosage form can be prepared for immediate release or controlled release. The dosage form can be a tablet, capsule, caplet, encapsulated pellets, encapsulated granules, powder, or encapsulated powder. These dosage forms can be provided as unit dosage forms.
The progesterone dosage forms of this invention comprise progesterone from about 25 mg to about 500 mg per dose. The therapeutic serum levels achieved may range from about 0.1 nanogram/ml (ng/ml) to about 400 ng/ml or more. The solid oral dosage forms provide a normalized Cmax of greater than about 0.1 ng/ml/mg. In some aspects, the normalized Cmax may range from about 0.15 ng/ml/mg to about 0.6 ng/ml1mg. In some other aspects, the normalized Cmax may range from about 0.2 ng/ml/mg to about 0.5 ng/ml/mg.
The progesterone dosage forms may also provide a normalized AUC(0-24) greater than about 0.5 ng.hr/ml/mg. In some aspects, the normalized AUC(0-24) may range from about 0.5 ng.hr/ml/mg to about 1.5 ng.hr/ml/mg. In some other aspects, the normalized AUC(0-24) may range from about 0.7 ng.hr/ml/mg to about 1.3 ng.hr/ml/mg. The AUC and other therapeutic levels projected in the application are now superseded by post-filing experimentation that is being made of record in the prosecution history, which provides the more recent experimental data upon which the public should rely. This data is not introduced into the patent specification because of the proscription of entry of new matter under 35 USC xc2xa7 132.
In some preferred aspects, the polyethylene glycol is polyethylene glycol 1450, polyethylen glycol 3350 or polyethylene glycol 8000, or a mixture thereof.
In some aspects, the cellulose ether is a hydroxyalkyl cellulose, carboxyalkyl cellulose, or a mixture thereof. In some preferred aspects, the cellulose ether is hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate trimellitate, or a mixture thereof.
In one specific aspect, an oral progesterone unit dosage form is provided which comprises micronized progesterone and a solid polymeric carrier, wherein the dosage form, upon oral administration, provides a therapeutically effective amount of progesterone to a subject, wherein, the dosage form comprises from about 25 mg to about 500 mg of micronized progesterone per dose; the solid polymeric carrier constitutes from about 45% to about 65% weight of the dosage form and comprises a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000.
In another specific aspect, a combination dosage form is provided which comprises an oral progesterone dosage form and an estrogen dosage form, wherein the combination dosage form is a capsule which encloses the progesterone dosage form and the estrogen dosage form;
the oral progesterone dosage form is a caplet comprising micronized progesterone and a solid polymeric carrier, which progesterone dosage form, upon oral administration, provides a therapeutically effective amount of progesterone to a subject, and the progesterone dosage form comprises from about 25 mg to about 500 mg of micronized progesterone per dose and the solid polymeric carrier constitutes from about 45% to about 65% weight of the progesterone dosage form and comprises a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000, and the therapeutically effective amount of progesterone represents a blood concentration of from about 0.1 ng/ml to about 400 ng/ml;
and the oral estrogen dosage form is an estradiol tablet comprising estradiol from about 0.25 mg to about 5 mg of estradiol.
This invention further provides a hormone replacement therapy by administering a dosage form described above to a subject in need of progesterone or a combination of progesterone and estrogen. The method of this invention may be used for treating or preventing various conditions, including, but not limited to, infertility related to non-receptive uterus, premenstrual tension, ovulation, primary dysmenorrhea and endometriosis, habitual abortion, respiratory depression in the Picklwickian syndrome, secondary amenorrhea, dysfunctional uterine bleeding, preeclampsia and toxemia of pregnancy, sexual infantilism, and post-menopausal symptoms.